The diazo route to diazonamide A. Studies on the indole bis-oxazole fragment

[structure: see text] Various approaches to the indole bis-oxazole fragment of the marine secondary metabolite diazonamide A are described, all of which feature dirhodium(II)-catalyzed reactions of diazocarbonyl compounds in key steps. Thus, 3-bromophenylacetaldehyde is converted into an alpha-diazo-beta-ketoester, dirhodium(II)-catalyzed reaction of which with N-Boc-valinamide resulted in N-H insertion of the intermediate rhodium carbene to give a ketoamide that readily underwent cyclodehydration to give (S)-2-(1-tert-butoxycarbonylamino)-2-methylpropyl]-5-(3-bromobenzyl)oxazole-4-carboxamide, after ammonolysis of the initially formed ester. This aryl bromide was then coupled to a 3-formyl-indole-4-boronate under Pd catalysis to give the expected biaryl. Subsequent conversion of the aldehyde group into a second alpha-diazo-beta-ketoester gave a substrate for an intramolecular carbene N-H insertion, although attempts to effect this cyclization were unsuccessful. A second approach to an indole bis-oxazole involved an intermolecular rhodium carbene N-H insertion, followed by oxazole formation to give (S)-2-[1-tert-(butoxycarbonylamino)-2-methylpropyl]-5-methyloxazole-4-carboxamide. A further N-H insertion of this carboxmide with the rhodium carbene derived from ethyl 2-diazo-3-[1-(2-nitrobenzenesulfonyl)indol-3-yl]-3-oxopropanoate gave a ketoamide, cyclodehydration of which gave the desired indole bis-oxazole. Finally, the boronate formed from 4-bromotryptamine was coupled to another diazocarbonyl-derived oxazole to give the corresponding biaryl, deprotection and cyclization of which produced a macrocyclic indole-oxazole derivative. Subsequent oxidation and cyclodehydration incorporated the second oxazole and gave the macrocyclic indole bis-oxazole.     

Control of competing N-H insertion and Wolff rearrangement in dirhodium(II)-catalyzed reactions of 3-indolyl diazoketoesters. synthesis of a potential precursor to the marine 5-(3-indolyl)oxazole martefragin A

Dirhodium(II)-catalyzed reaction of 3-indolyl alpha-diazo-beta-ketoester 25 in the presence of hexanamide results in competing metal carbene N-H insertion and Wolff rearrangement. The corresponding phenyl diazoketoester 32, on the other hand, gives only the product of N-H insertion, suggesting that the indole moiety is more prone to 1,2-rearrangement. The competing processes were investigated in a range of 3-indolyl alpha-diazo-beta-ketoesters (36, 38, 40, 44); these studies established that the Wolff rearrangement could be effectively suppressed by the presence of a strong electron-withdrawing group on the indole nitrogen. Dirhodium(II) catalysts were also more effective than copper or Lewis acid catalysts in favoring the insertion process. The products of N-H insertion, the ketoamides (26, 47, 49, 51, 53), were readily cyclodehydrated to the corresponding 5-(3-indolyl)oxazoles. The N-H insertion/cyclodehydration methodology was used in a formal synthesis of the marine natural product martefragin A. Thus the N-Boc homoisoleucine amide 23, prepared by asymmetric hydrogenation of a dehydro amino acid, underwent N-H insertion with the rhodium carbene derived from the N-nosyl indolyl diazoester 40, followed by cyclodehydration and deprotection to give the 5-(3-indolyl)oxazole martefragin A precursor 75.     

Immobilized alpha-diazophosphonoacetate as a versatile key precursor for palladium catalyzed indole synthesis on a polymer support

Rh(II)-catalyzed N-H insertion reaction of immobilized alpha-diazophosphonoacetate with 2-haloanilines followed by Horner-Emmons reaction gave immobilized enaminoesters, which were efficiently cyclized to indoles via intramolecular palladium catalyzed reaction on a polymer support.     

Asymmetric synthesis of the central tryptophan residue of stephanotic acid

The C-6 substituted tryptophan di- and tri-peptides and , representing the tryptophan core of stephanotic acid, have been synthesized, the key steps being the formation of the phosphono-di- and tri-peptides and by a highly chemoselective rhodium(II) catalyzed carbene N-H insertion reaction, their subsequent Horner-Wadsworth-Emmons reactions with N-Boc-6-bromoindole-3-carboxaldehyde, and the rhodium(I) catalyzed asymmetric hydrogenation of the resulting dehydro di- and tri-peptides.     

Cycloaddition chemistry of 2-vinyl-substituted indoles and related heteroaromatic systems

[reaction: see text] The intramolecular Diels-Alder cycloaddition reaction (IMDAF) of several N-phenylsulfonylindolyl-substituted furanyl carbamates containing a tethered pi-bond on the indole ring were examined as an approach to the iboga alkaloid catharanthine. Only in the case where the tethered pi-bond contained two carbomethoxy groups did the [4 + 2]-cycloaddition occur. Push-pull dipoles generated from the Rh(II)-catalyzed reaction of diazo imides, on the other hand, undergo successful intramolecular 1,3-dipolar cycloaddition across both alkenyl and heteroaromatic pi-bonds to provide novel pentacyclic compounds in good yield and in a stereocontrolled fashion. The facility of the cycloaddition was found to be critically dependent on conformational factors in the transition state. Ligand substitution in the rhodium(II) catalyst markedly altered the product ratio between [3 + 2]-cycloaddition and intramolecular C-H insertion. The variation in reactivity reflects the difference in electrophilicity between the various rhodium carbenoid intermediates. Intramolecular C-H insertion is enhanced with the more electrophilic carbene generated using Rh(II) perfluorobutyrate.     

Rhodium carbenoid N-H insertion reactions of primary ureas: solution and solid-phase synthesis of imidazolones

[reaction: see text] The solution and solid-phase synthesis of imidazolones is reported. The key step for the preparation of these compounds is the N-H insertion reaction of primary ureas into highly reactive rhodium carbenoid intermediates. Typically, a soluble or support-bound alpha-diazo-beta-ketoester is treated with a rhodium carboxylate catalyst in the presence of a primary urea to give the corresponding N-H insertion product. Subsequent acid-catalyzed cyclodehydration of these insertion products affords the desired imidazolone products.     

Ligand effects in the Rh(II) catalyzed reaction of α-diazo ketoamides

The rhodium(II) catalyzed decomposition of several α-diazo ketoamides resulted in either formation of a push-pull carbonyl ylide intermediate followed by intramolecular [3+2]-cycloaddition across the tethered π-bond or C-H insertion of the initially formed rhodium carbenoid into the C₅-position of the lactam ring followed by a carboethoxy-decarboxylation reaction. The chemoselectivity exhibited by the rhodium carbenoid intermediate was found to be markedly dependent on the metal ligands employed.     

Convenient preparation of indolyl Malonates via Carbenoid insertion

Indoles, when treated with methyldiazomalonate under catalysis by rhodium(II)acetate, undergo C-H and N-H insertion reactions regioselectively depending on the substitution pattern on the indole moiety. In indoles where the 3-position is unsubstituted, high yields of the C3-H insertion product were observed. In 3-alkylindoles, 2-substitution predominated, while N-methyltetrahydrocarbazole yielded the product resulting from insertion into the C6-H bond. Indoles in which the nitrogen is unprotected yield varying degrees of N-H insertion.     

Total synthesis of stephanotic acid methyl ester

[structure: see text]The methyl ester of the naturally occurring macrocyclic pentapeptide stephanotic acid, containing an unusual beta-substituted alpha-amino acid with a tryptophan C-6 to leucine beta-carbon link, has been synthesized. The key steps include the formation of this amino acid through a thioxo-oxazolidine intermediate and a Horner-Wadsworth-Emmons reaction using a phosphonoglycine, derived by a dirhodium(II)-catalyzed N-H insertion reaction, to give a dehydroamino acid and subsequent rhodium(I)-catalyzed asymmetric hydrogenation to introduce the modified tryptophan residue.     

Synthesis of phthalan and phenethylamine derivatives via addition of alcohols to rhodium(II)-azavinyl carbenoids

1-Sulfonyl-1,2,3-triazoles undergo inter- and intramolecular 1,3-OH insertion with rhodium(II)-azavinyl carbenoid intermediates upon treatment with a rhodium(II) catalyst. Products of this transformation contain a synthetically versatile N-(2-alkoxyvinyl)sulfonamide, enabling divergent reactivity toward several N-protected phenethylamine derivatives under various conditions. Notably, products with a phthalan framework can be accessed directly from 4-aryl-1-sulfonyl-1,2,3-triazoles bearing a pendant alcohol.     

Asymmetrische Katalysen, 58. Mitt.: Enantioselektive S - H- und C - H-Insertionen mit optisch aktiven Rh(II)- und Cu(II)-Katalysatoren

Summary The substrates for the S - H insertion reaction were azibutanone2 and thiophenol3. Methyl 2-diazo-3-oxo-heptane-carboxylate26 was used as the substrate in an intramolecular C - H insertion. Both reactions were carried out enantioselectively in the presence of optically active rhodium(II) and copper(II) catalysts. For the S - H insertion optical inductions up to 13.8%ee and for the C - H insertion up to 14%ee were achieved.

     

Asymmetric synthesis of cis-5-tert-butylproline with metal carbenoid NH insertion

The highly stereoselective intramolecular metal carbenoid insertion reaction of sulfinimine-derived delta-amino alpha-diazoesters is used to prepare cis-5-tert-butylproline. A concerted or nearly concerted metal carbenoid N-H insertion reaction mechanism is proposed.     

Highly diastereoselective addition of the lithium enolate of alpha-diazoacetoacetate to N-sulfinyl imines: enantioselective synthesis of 2-oxo and 3-oxo pyrrolidines

The highly enantioselective synthesis of 2-oxo and 3-oxo pyrrolidines has been achieved by diastereoselective addition of the lithium enolate of alpha-diazoacetoacetate to chiral N-sulfinyl imines, followed by photoinduced Wolff rearrangement or Rh(II)-catalyzed intramolecular N-H insertion.     

Rhodium phosphine-π-arene intermediates in the hydroamination of alkenes

A detailed mechanistic study of the intramolecular hydroamination of alkenes with amines catalyzed by rhodium complexes of a biaryldialkylphosphine is reported. The active catalyst is shown to contain the phosphine ligand bound in a κ(1), η(6) form in which the arene is π-bound to rhodium. Addition of deuterated amine to an internal olefin showed that the reaction occurs by trans addition of the N-H bond across the C═C bond, and this stereochemistry implies that the reaction occurs by nucleophilic attack of the amine on a coordinated alkene. Indeed, the cationic rhodium fragment binds the alkene over the secondary amine, and the olefin complex was shown to be the catalyst resting state. The reaction was zero-order in substrate, when the concentration of olefin was high, and a primary isotope effect was observed. The primary isotope effect, in combination with the observation of the alkene complex as the resting state, implies that nucleophilic attack of the amine on the alkene is reversible and is followed by turnover-limiting protonation. This mechanism constitutes an unusual pathway for rhodium-catalyzed additions to alkenes and is more closely related to the mechanism for palladium-catalyzed addition of amide N-H bonds to alkenes.     

Rhodium(II)‐ or Copper(I)‐Catalyzed Formal Intramolecular Carbene Insertion into Vinylic C(sp2)−H Bonds: Access to Substituted 1H‐Indenes

A rhodium(II)‐ or copper(I)‐catalyzed formal intramolecular carbene insertion into vinylic C(sp²)−H bonds is reported herein. This method provides straightforward access to 1H ‐indenes with high efficiency and excellent functional‐group compatibility. Mechanistically, the reaction is proposed to involve the following sequence: metal carbene formation, intramolecular nucleophilic addition of the double bond to the electron‐deficient carbene carbon atom, dearomatization, and finally a 1,5‐H shift.     

α-重氮羰基化合物分解反应的机理以及合成应用

本项工作应用物理有机化学的经典方法-Hammett线性自由能相关,对在有机合成中已得到广泛应用的Rh(Ⅱ)-卡宾分子内C-H插入反应的机理进行了深入的探讨。在α-重氮羰基化合物的合成应用方面,发现了Cu(acac)2可以有效地催化α-重氮羰基化合物分解并发生选择的分子内N-H键插入反应。此外,应用α-重氮羰基化合物在Ag(Ⅰ)催化剂的作用下的Wolff重排反应可以有效地合成光学纯的α-内酰胺。     

Rhenium-catalyzed formation of indene frameworks via C-H bond activation: [3+2] annulation of aromatic aldimines and acetylenes

A rhenium complex, [ReBr(CO)3(thf)]2, catalyzes the reaction of an aromatic aldimine with an acetylene to give an indene derivative in a quantitative yield. The reaction proceeds via C-H bond activation, insertion of the acetylene, intramolecular nucleophilic cyclization, and reductive elimination. In contrast to ruthenium and rhodium catalysts, which are usually employed in this type of reaction, the rhenium catalyst promotes the intramolecular nucleophilic cyclization of the alkenylmetal species generated by insertion of the acetylene.     

Catalyst‐Controlled Regiodivergent Alkyne Insertion in the Context of C−H Activation and Diels–Alder Reactions: Synthesis of Fused and Bridged Cycles

Rhodium(III)‐ and cobalt(III)‐catalyzed C−H activation of indoles and coupling with 1,6‐enynes is discussed. Under rhodium(III) catalysis, the alkyne insertion follows 2,1‐regioselectivity with a subsequent type‐I intramolecular Diels–Alder reaction (IMDA) to afford [6,5]‐fused cycles. When catalyzed by the cobalt(III) congener, 1,2‐insertion of the alkyne is preferred, and followed by a rare type‐II IMDA, thus leading to bridged [3,3,1]‐cycles. This selectivity of the alkyne insertion was mainly tuned by the steric sensitivity of the catalyst.     

Enantiospecific total synthesis of (-)-4-thiocyanatoneopupukeanane

Enantiospecific synthesis of the natural enantiomer of the marine sesquiterpene (-)-4-thiocyanatoneopupukeanane (6) is described. The bicyclo[2.2.2]octanecarboxylate 14, obtained from (R)-carvone via Michael-Michael reaction, was transformed into neopupukeananedione 12 by employing rhodium acetate catalyzed intramolecular C-H insertion of the diazo ketones 16 or 19 as the key reaction. Regioselective deoxygenation of the C-2 ketone transformed the dione 12 into neopupukean-4-one 10. Alternately, the keto ester 18 was also transformed into neopupukean-4-one 10 via regioselective deoxygenation of the ketone in 18 followed by intramolecular rhodium carbenoid C-H insertion of the diazo ketone 31. Finally, neopupukean-4-one 10 was transformed into (-)-4-thiocyanatoneopupukeanane 6 via the alcohol 32 and the mesylate 33.     

The bis(trimethylsilyl)methyl group as an effective N-protecting group and site-selective control element in rhodium(II)-catalyzed reaction of diazoamides

The intramolecular rhodium(II)-carbenoid-mediated C-H insertion reaction of structurally varied N-bis(trimethylsilyl)methyl,N-substituted diazoamides is studied. It has been found that in tertiary diazoamides the N-bis(trimethylsilyl)methyl (N-BTMSM) group is effective for conformational control about the amide N-C(O) bond; C-H insertion occurs at the other N-substituent. In C(alpha)-branched diazoamides, the N-BTMSM is found also to exert its influence on the conformational preference about the N-C(alpha) bond, which affects the regioselectivity of the C-H insertion in these systems. In unbranched diazoamides, inherent electronic effects of the N-substituent affect the regio- and chemoselectivity of the reaction; however, in branched diazoamides, electronic effects of the N-substituent and the alpha-substituent at the carbenoid carbon are subtle, but important in the deciding the eventual outcome of the reaction.